213766-03-1Relevant articles and documents
2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: Synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling
Koren, Andrei O.,Horti, Andrew G.,Mukhin, Alexey G.,Gündisch, Daniela,Kimes, Alane S.,Dannals, Robert F.,London, Edythe D.
, p. 3690 - 3698 (2007/10/03)
3-(2(S)-Azetidinylmethoxy)pyridine (A-85380) has been identified recently as a ligad with high affinity for nicotinic acetylcholine receptors (nAChRs). Here we report the synthesis and in vitro nAChR binding of a series of 10 pyridine-modified analogues of A-85380. The novel compounds feature a halogen substituent at position 2, 5, or 6 of the 3-pyridyl fragment. Those with the substituents at position 5 or 6, as well as the 2-fluoro analogue, possess subnanomolar affinity for nAChRs in membranes from rat brain. For these ligands, K(i) values range from 11 to 210 pM, as measured by competition with (±)-[3H]epibatidine. In contrast, 2-chloro, 2-bromo, and 2-iodo analogues exhibit substantially lower affinity. AM1 quantum chemical calculations demonstrate that the bulky substituents at position 2 cause notable changes in the molecular geometry. The high-affinity members of the series and (+)-epibatidine display a tight fit superposition of low-energy stable conformers. The new ligands with high affinity for nAChRs may be of interest as pharmacological probes, potential medications, and candidates for developing radiohalogenated tracers to study nAChRs.
